Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia (A Central University), New Delhi, India.
Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, India.
Mol Oncol. 2021 May;15(5):1450-1465. doi: 10.1002/1878-0261.12894. Epub 2021 Mar 13.
Striking similarity exists between metabolic changes associated with embryogenesis and tumorigenesis. Chromobox proteins-CBX2/4/6/7/8, core components of canonical polycomb repressor complex 1, play essential roles in embryonic development and aberrantly expressed in breast cancer. Understanding how altered CBX expression relates to metabolic reprogramming in breast cancer may reveal vulnerabilities of therapeutic pertinence. Using transcriptomic and metabolomic data from breast cancer patients (N > 3000 combined), we performed pathway-based analysis and identified outstanding roles of CBX2 and CBX7 in positive and negative regulation of glucose metabolism, respectively. Genetic ablation experiments validated the contrasting roles of two isoforms in cancer metabolism and cell growth. Furthermore, we provide evidence for the role of mammalian target of rapamycin complex 1 signaling in mediating contrary effects of CBX2 and CBX7 on breast cancer metabolism. Underpinning the biological significance of metabolic roles, CBX2 and CBX7 were found to be the most up- and downregulated isoforms, respectively, in breast tumors compared with normal tissues. Moreover, CBX2 and CBX7 expression (not other isoforms) correlated strongly, but oppositely, with breast tumor subtype aggressiveness and the proliferation markers. Consistently, genomic data also showed higher amplification frequency of CBX2, not CBX7, in breast tumors. Highlighting the clinical significance of findings, disease-specific survival and drug sensitivity analysis revealed that CBX2 and CBX7 predicted patient outcome and sensitivity to FDA-approved/investigational drugs. In summary, this work identifies novel cross talk between CBX2/7 and breast tumor metabolism, and the results presented may have implications in strategies targeting breast cancer.
胚胎发生和肿瘤发生相关的代谢变化之间存在惊人的相似性。染色盒蛋白-CBX2/4/6/7/8 是经典多梳抑制复合物 1 的核心组成部分，在胚胎发育中发挥重要作用，并在乳腺癌中异常表达。了解 CBX 表达的改变如何与乳腺癌中的代谢重编程相关，可能揭示出具有治疗相关性的弱点。我们使用来自乳腺癌患者（总计超过 3000 例）的转录组和代谢组学数据，进行了基于途径的分析，并确定了 CBX2 和 CBX7 在分别正向和负向调节葡萄糖代谢中的突出作用。遗传缺失实验验证了两种异构体在癌症代谢和细胞生长中的相反作用。此外，我们提供了证据表明雷帕霉素复合物 1 信号通路在介导 CBX2 和 CBX7 对乳腺癌代谢的相反作用中发挥作用。为了证明代谢作用的生物学意义，我们发现与正常组织相比，CBX2 和 CBX7 分别是乳腺癌肿瘤中上调和下调最多的异构体。此外，CBX2 和 CBX7 的表达（而非其他异构体）与乳腺癌肿瘤亚型的侵袭性和增殖标志物强烈相关，但呈相反趋势。一致地，基因组数据还显示 CBX2 而不是 CBX7 在乳腺癌肿瘤中的扩增频率更高。强调发现的临床意义，疾病特异性生存和药物敏感性分析表明，CBX2 和 CBX7 预测患者的预后和对 FDA 批准/研究药物的敏感性。总之，这项工作确定了 CBX2/7 与乳腺癌代谢之间的新的交叉对话，并且提出的结果可能对靶向乳腺癌的策略具有重要意义。
